PROJECT ABSTRACT Breast cancer is the second leading cause of death in women. Doxorubicin, docetaxel and paraclitaxel are the most commonly used chemotherapeutic agents to treat breast cancer. Although these drugs have shown high efficacy and low toxicity in in vitro and in vivo studies, their therapeutic effects in humans have been hampered by several factors, including the important one of drug resistance (DR). There is an urgent need to develop new imaging and therapeutic approaches to mitigate this phenomenon. To this end we propose to develop a novel theranostic device that provides simultaneous imaging of drug delivery, retention, distribution, and therapeutic outcome tracking. It utilizes the highly customized patchy surface and tunable internal properties of semiconducting polymeric particles, which allow them to produce a multiplexing Photoacoustic effect between 550 and 1100 nm wavelength. The research aims for this R15 proposal are: Aim 1. Optimize external and internal properties of SPPP to enhance therapeutic and imaging efficacy, Aim 2. Assess in vitro the efficacy and toxicity of SPPP as theranostics devices, Aim 3. Assess in vivo the effectiveness of SPPP as theranostic devices. Our SPPP are made of poly-lactic-co-glycolic acid (PLGA) a biocompatible, biodegradable and FDA approved polymer, with lipid-polymer functional groups (LPFGs) and a non-toxic semiconducting polymer. They have unique patch-core-shell structural features, such as: hollow or solid hydrophobic polymeric cores and patchy surface. One of the greatest advantages of patchy particles is their proclivity to cluster, and thereby enhance the signal produced by the organic or inorganic molecules that chemically modify the LPFGs. Furthermore, these particles emit a Photoacoustic (PA) signal emitted a PA in the optimal imaging window (i.e., 700nm to 900 nm). The proposed engineered targeted cancer theranostics system will allow us to: a) optimize the external and internal PA properties of SPPP to render a multiplexing effect that can allow us to obtain substantial anatomical, physiological and functional information about the tumor, and b) assess the in vitro and in vivo imaging and therapeutic performance of SPPP.